Our studies of various virologic and immunopathologic processes that occur when viruses and parasites replicate in the ocular microenvironment comprise four areas: (1) virus induced retinal degenerative processes;(2) the possible roles of viruses in human diseases;(3) molecular diagnosis and pathogenesis of cytomegalovirus (CMV) infections in man;and (4) herpesvirus infections of the eye. We have established a model system for studying retinal degenerative diseases, experimental coronavirus retinopathy (ECOR). The virus is capable of inducing an acute infection in the presence of mild retinal vascular inflammation. Initial retinal damage is followed by clearance of infectious virus and progressive retinal degeneration. This is the first retinal model to demonstrate a virus induced degeneration, viral persistence, a genetic predisposition to virus induced tissue damage and a virus triggered autoimmune response. Our goal is to determine the pathophysiological mechanisms and to identify genes involved in the retinal degenerative disease. During the past year we have continued to evaluated very early cytokine and chemokine profiles as a measure of intensity of immune reactivity in coronavirus infected mice with a retinal degeneration susceptible and a retinal degeneration resistant background. These studies identified a distinct difference in the early immune response that is generated by the two mouse strains. These differences are noted in the production of IFN-gamma and the two chemokines triggered by IFN-gamma, CXCL9 and CXCL10. At day 2 and 3 PI, BALB/c mice have high levels of IFN-gamma, CXCL9 and CXCL10 in their sera. At the same time, significantly lower levels of these molecules are detected in sera from CD-1 mice. Moreover, real time PCR analysis of retinas identified that CXCL9 and CXCL10 gene expression is significantly greater in retinas from BABL/c mice in comparison to CD-1 mice. These studies identify possible mechanisms that allow the BALB/c mouse to have a robust immune response that could trigger an autoimmune component. CXCL9 and CXCL10 are potent chemokines that interact with CXCR3 present on activated T cells and NK cells.These T cells participate in immune reactivity against infected and self targets within the retina. Corneal herpes infection elicits a robust inflammatory response and eventually leads to a vision-threatening stromal keratitis as a sequela of frequent reactivation of latent virus. The aetiology of herpetic stromal keratitis (HSK) is thought to be an aberrant TH1 cytokine mediated immunopathology. Recently, we identified that the continued presence of HSV-DNA and HSV-IgG IC within the ocular microenvironment may contribute to angiogenesis and inflammation observed in HSK, and cytokines and TLRs may be potential targets for intervention. During the past year we have determined the association of HHV-6 and/or other human herpesviruses in corneal inflammation using polymerase chain reaction (PCR). We evaluated 22 patients with corneal inflammation. Among them, HHV-6 was positive in 14 out of 22 patients, and HSV-1 was found in 9 of those patients. Only 5 patients were negative for herpesvirus DNA. These results indicated that the majority of the corneal inflammation was related to herpesviruses, and that the association of HHV-6 with disease was more frequent that with other herpesviruses. In contrast, HHV-6 DNA was not detected in 47 tear samples obtained from normal individuals. When HSV-1 triggers corneal inflammation, infiltrated T cells or macrophages may carry HHV-6. The immune suppressive activities induced by HHV-6 may further facilitate HSV-1 replication. We also observed HHV-6 but not HSV-1 DNA in smear samples from 5 of 12 patients. These latter data indicate that HHV-6 may be another causative agent by itself in corneal inflammation. The issue of whether HHV-6 is a bystander or true pathological agent remains to be further elucidated.